The present invention relates to biodegradable anionic polycarbonates and polyarylates having pendent carboxylic acid groups, and to block copolymers thereof with poly(alkylene oxides). The present invention further relates to species of the above-listed polymers having pendent carboxylic acid ester groups, and, more specifically, to pendent benzyl ester groups and the selective removal of such benzyl esters to form pendent carboxylic acid groups by palladium (Pd)-catalyzed hydrogenolysis of the benzyl esters. The present invention further relates to polycarbonates, polyarylates, and poly(alkylene oxide) block copolymers thereof that are homopolymers and copolymers of tyrosine-derived diphenol monomers having pendent benzyl carboxylate groups.
Diphenols are monomeric starting materials for polycarbonates, polyiminocarbonates, polyarylates, polyurethanes, and the like. Commonly owned U.S. Pat. Nos. 5,099,060 and 5,198,507 disclose amino acid-derived diphenol compounds, useful in the polymerization of polycarbonates and polyiminocarbonates. The resulting polymers are useful as degradable polymers in general, and as tissue-compatible bioerodible materials for medical uses, in particular. The suitability of these polymers for this end use application is the result of their polymerization from diphenols derived from the naturally occurring amino acid, L-tyrosine. The disclosures of U.S. Pat. Nos. 5,099,060 and 5,198,507 are hereby incorporated by reference. These previously-known polymers are strong, water-insoluble materials that can best be used as structural implants.
The same monomeric L-tyrosine derived diphenols were also used in the synthesis of polyarylates as described in commonly owned U.S. Pat. No. 5,216,115, and in the synthesis of poly(alkylene oxide) block copolymers with the aforementioned polycarbonates and polyarylates, which is disclosed in commonly owned U.S. Pat. No. 5,658,995. The disclosures of U.S. Pat. Nos. 5,216,115 and 5,658,995 are also hereby incorporated by reference.
The polycarbonates, polyarylates and poly(alkylene oxide) block copolymers thereof cannot be prepared by conventional solution processes from monomers having free carboxylic acid groups. Therefore, one must selectively incorporate removable protecting groups that can be cleaved after the polymer is formed, without significant degradation of the polymer backbone. The protecting groups are needed to prevent cross-reaction of these otherwise free carboxylic acid groups (i) with the phosgene used in the preparation of polycarbonates and (ii) with the carbodiimide reagents used in the preparation of polyarylates.
The resulting polymers with protected carboxylic acid groups are limited in application because of their slow rate of degradation and significant hydrophobicity. The free acid form of the polymers, in which the ester protecting groups have been removed from the pendent carboxylic acid chains of the diphenols, would be less hydrophobic and thus would be expects to exhibits somewhat increased degradation rates.
In polycarbonates, polyarylates and poly(alkylene oxide) block copolymers thereof prepared from tyrosine-derived diphenol monomers, the backbone contains bonds that are designed to degrade in aqueous media (acidic, neutral, or basic). Thus, the selective removal of any carboxylic acid protecting groups is a challenge. For polyarylates and poly(alkylene oxide) block copolymers thereof, the ester protecting groups cannot be removed by conventional hydrolysis techniques without complete degradation of the polymer backbone. For polycarbonates and poly(alkylene oxide) block copolymers thereof, the ester protecting groups cannot be removed by conventional hydrolysis techniques without massive degradation of the polymer backbone. Since cleavage of the pendent ester groups becomes slower (relative to backbone cleavage) as the bulkiness of the pendent group increases, conventional hydrolysis of methyl and ethyl ester pendent chains is accompanied by a dramatic loss of molecular weight, while attempts to remove bulkier ester pendent chains by either basic or acidic hydrolysis of polycarbonates results in total destruction of the polymer and the recovery of oligomeric species only. Thus, conventional hydrolysis of polycarbonates and poly(alkylene oxide) block copolymers thereof is of marginal value if applied to methyl or ethyl ester pendent chains and is entirely unsuitable for the removal of bulkier pendent chains.
There exist several needs that can be addressed by the incorporation of free carboxylic acid groups to the above mentioned polymer systems. First, the presence of free carboxylic acid groups on polymeric surfaces allows for the modification of the surface properties via the chemical attachment of selected pendent chains, the attachment of biologically active molecules, or the attachment of drugs moieties. Second, the presence of free carboxylic acid groups by itself is a strong regulator of cell attachment, growth and migration on polymeric surfaces. This is of particular importance in the design of medical implant materials that are used in tissue engineering applications where the exact control of cell attachment, spreading and proliferation is a key to the success of the tissue engineering implant.
There exists a need for degradable, biocompatible polymer systems whose design includes the convenient formation of a pendent carboxylic acid group at each monomeric repeat unit without significant backbone degradation. A second need is the need to control the polymer degradation rate through small changes in polymer composition.